FR2920311A1 - SOLID COMPOSITION, ORODISPERSIBLE AND / OR DISPERSIBLE, WITHOUT A KNOWLEDGE EXCIPIENT AND PROCESS FOR PREPARING THE SAME - Google Patents

Abstract

The present invention relates to a solid, orodispersible and / or dispersible composition comprising (a) from 0.1 to 60% by weight of at least one active substance; (b) from 40 to 99% by weight of at least one diluent with no known effect; (c) from 0.1 to 15% by weight of at least one disintegrating agent; and (d) from 0.05 to 10% by weight of at least one sweetening agent with a particle size of less than 50 μm, the percentages by weight being expressed relative to the total weight of said composition. The present invention also relates to the use of said composition as a medicament, as a dietary supplement or in cosmetics and a process for preparing an orodispersible and / or dispersible compound using said composition.

Description

SOLID COMPOSITION, ORODISPERSIBLE AND / OR DISPERSIBLE, WITHOUT A KNOWLEDGE EXCIPIENT AND PROCESS FOR PREPARING THE SAME

TECHNICAL FIELD The present invention relates to the field of pharmaceutical, cosmetic, parapharmaceutical, nutraceutical, food and agri-food compositions, as well as to their methods of preparation.

More particularly, the present invention relates to a solid composition, without excipient with known effect, disintegrating in the oral cavity or under the tongue in less than 20s, or dispersing in water without prior stirring in less than 3 min, obtained according to a simple method of preparation that does not alter the physicochemical and pharmacokinetic properties of the active substance (s) present in the composition. The active substance (s) present in the composition may be of hydrophilic, hydrophobic or amphiphilic nature, their average particle size distribution does not advantageously exceed 50 μm. The composition free of excipient with known effect, object of the present invention requires no coating or filming to mask the bad taste or bitterness of certain active substances.

The simple method of preparation guarantees the industrial feasibility of a homogeneous, stable and non-friable composition. STATE OF THE PRIOR ART For improved patient comfort and better compliance, various immediate-release compositions disintegrating in the oral cavity have been placed on the market.

Thus, there are preparations in the form of oral lyophilisate. These forms have the advantage of being disintegrated rapidly despite the poor solubility of the active substance, but the process for producing such a form requiring a freeze-drying step is complex and expensive. The compositions obtained are, in general, friable and require moisture-protective packaging to guarantee their integrity. Moreover, once disintegrated, the grains dispersed in the oral cavity confer a gritty and floury feeling particularly uncomfortable To avoid the freeze-drying step, it has been proposed to produce orodispersible tablets. The numerous patented technologies (OraSolv, DuraSolv, Flash Dose, WowTab, FlashTab, OraQuick ...) and manufacturing processes around this galenic form are numerous, they try to solve 3 main problems. the time of disintegration of the tablet in the oral cavity, without the addition of water, is less than 3 minutes as recommended in the various pharmacopoeias in force. To this problem is added the fact that, from one individual to another, the quantity of saliva present in the oral cavity is variable; obtaining tablets with acceptable hardness and friability characteristics to maintain good disintegration properties; - the masking of bitterness or bad taste of many active ingredients.

To solve the problem of disintegration, several techniques are described in the prior art, such as the use of soluble excipients, super-disintegrating agents or effervescent couples. The international application WO 00/27357 describes a multiparticulate tablet orodispersible capable of disintegrating in less than 40 seconds, based on polyol.

US Patent Application No. 2003147947 discloses a composition of lactose granule and co-dried starch (StarLacTM). The OraSoly technology of Cima Labs produces a tablet that disintegrates rapidly in the oral cavity using low effervescence. To solve friability problems, international application WO 2004/043440 uses a polysaccharide produced from a yeast that is pullulan and tablets, whose friability is less than 1%, are obtained by a method of freeze drying. either fusion-molding.

In order to increase the hardness of orodispersible tablets, US Pat. No. 6,024,981 uses a diluent which is not suitable for direct compression, the orodispersible tablets thus obtained having a hardness of between 15 and 50 N. Patent application EP 1156786 teaches tablets that are slightly friable by means of the use of a lubricating agent on the surface of the tablets. For taste masking, the FlashTab technology described by Ethypharm in patent application EP 1441704 relates to orodispersible tablets based on microcrystals or microgranules of coated active ingredient. The major disadvantage of these compositions is the presence of excipients with known effect which, therefore, entail risks of intolerance in certain categories of patients. Likewise, these various patented technologies require conditions of manufacture and storage of products with a controlled atmosphere, given the highly hygroscopic nature of the powders generated by these processes and compositions. To solve this drawback, the international application WO 2005/034921 teaches an orodispersible composition based on a sparingly soluble or insoluble neurological agent preferably using, as a diluent for sugars, but which may optionally comprise as diluting agent microcrystalline cellulose or dextrate, excipients without known effect. However, to ensure the stability of the composition a stabilizing agent is needed. In addition, the preferred embodiment incorporates a wet granulation step. International Application WO 2004/091585 discloses an oral disintegrating composition based on silicified microcrystalline cellulose such as Prosolv. This type of microcrystalline cellulose guarantees the stability of the composition but is particularly expensive. In addition, the silicified microcrystalline cellulose can not be used with all the active substances because of incompatibility. There is a need, in the state of the art, to develop an orodispersible composition and a simple method of preparation thereof that does not have the known technical disadvantages for the orodispersible compositions of the prior art. PRESENTATION OF THE INVENTION The work of the Applicant has made it possible to develop an orodispersible solid composition without excipient with known and non-hygroscopic effect and its preparation process, both of which make it possible to meet the technical drawbacks mentioned above. In addition, the solid orodispersible composition object of the present invention is remarkable in that it applies to different technical fields. Indeed, this composition can be a pharmaceutical, cosmetic, parapharmaceutical, nutraceutical, food or agri-food composition. The solid composition object of the present invention is also remarkable in that it has the appropriate characteristics not only for an orodispersible composition but also for a dispersible composition. The composition which is the subject of the present invention therefore constitutes an orodispersible and / or dispersible composition.

The solid, orodispersible and / or dispersible composition that is the subject of the present invention is in the form of an uncoated tablet, which disintegrates rapidly in the oral cavity or under the tongue, or which breaks up rapidly in a glass of water without alteration. pharmacokinetic properties of the active substance (s) present in the composition, said tablet being obtained according to a simple method of preparation. The active substance (s) present in the composition may be hydrophilic, hydrophobic or amphiphilic in nature, their average particle size advantageously not exceeding 50 μm. The characteristics of the solid, orodispersible and / or dispersible composition according to the invention have been achieved thanks to the development of a particular combination of a substance (s) active with excipients having particular features and the use of a manufacturing process comprising successive dilution steps and then a direct compression step. The composition object of the present invention is free of excipient with known effect and inexpensive. The particles of active substance (s) do not require coating or filming to mask their unpleasant flavors. The composition which is the subject of the present invention advantageously does not comprise a stabilizing agent. The simple preparation method, object of the present invention, guarantees the industrial feasibility of a homogeneous, stable and non-friable composition by a process comprising several dilution steps, then a direct compression step. In the context of the present invention, the term "homogeneous composition" is intended to mean any composition which satisfies the uniformity test for the content of single-dose preparations as described in the European Pharmacopoeia in force, namely an individual content of each unit included between 85 and 115% of the average content. In the context of the present invention, a stable composition is understood to mean any composition retaining these initial characteristics after having been subjected to an ICH stability study. In the context of the present invention, the term "non-friable composition" is intended to mean any composition which satisfies the friability test described in the current European Pharmacopoeia, namely a maximum mass loss of 1%. The present invention relates more particularly to a solid, orodispersible and / or dispersible composition, without excipient with known effect, comprising: a) from 0.1 to 60% by weight of at least one active substance; b) from 40 to 99% by weight of at least one diluent with no known effect; c) from 0.1 to 15% by weight of at least one disintegrating agent; and d) from 0.05 to 10% by weight of at least one sweetening agent with a particle size less than 50 μm, the percentages by weight being expressed relative to the total weight of said composition.

In the context of the present invention, the term "orodispersible composition" is intended to mean an uncoated tablet intended to be placed in the mouth or under the tongue where it disperses rapidly before being swallowed (European Pharmacopoeia 5.8). An orodispersible tablet disintegrates or disintegrates in water at 37 ° C in less than 3 minutes. Better still, thanks to the invention, it disintegrates in less than 2 minutes, especially in less than 1 minute, in particular, in less than 30 seconds and, more particularly, in less than 20 seconds. In the context of the present invention, the term "dispersible composition" is intended to mean an uncoated tablet intended to be dispersed in water before administration to form a homogeneous dispersion (European Pharmacopoeia 5.8). A dispersible tablet disintegrates in water at 15-25 ° C in less than 3 minutes, without prior agitation. Better still, thanks to the invention, it disintegrates in less than 2 minutes, especially in less than 1 minute, in particular, in less than 30 seconds and, more particularly, in less than 20 seconds. The homogeneous dispersion obtained must be able to pass through a sieve with a nominal mesh size of 710 μm. In the context of the present invention, the term "excipient with known effect" means any composition that does not require any precaution for use for certain particular categories of patients. In particular, the polyol, such as mannitol, xylitol, sorbitol, maltitol, maltitol syrup, isomalt, aspartame, etc. and any other excipient mentioned in the list of excipients will be excluded from the composition according to the invention. noticeable effect and likely to cause intolerance. Thus, the composition according to the invention also excludes boric acid and its salts at a dose greater than 3 mg / kg / day; wheat starch; bronopol at a dose greater than 0.05% (percentage by weight expressed relative to the total weight of the composition); benzalkonium chloride; organomercury compounds; ethanol at a dose greater than 0.05 g / day; formaldehyde at a dose greater than 0.05% (percentage by weight expressed relative to the total weight of the composition); fructose; galactose; glucose; glycerol at a dose greater than 1 g / dose or greater than 3 g / 24 hours; peanut oil; castor oil and its derivatives; soybean oil and its derivatives; sesame oil; lactose; paraformaldehyde at a dose greater than 0.5% (percentage by weight expressed relative to the total weight of the composition); polyethylene glycol at a dose greater than 2 g / dose or greater than 6 g / day; phenylalanine; potassium; sucrose; sodium at a dose greater than 200 mg / day for compositions intended for adults; invert sugar; sulphites and metabisulfites; tartrazine and azo dyes.

The solid orodispersible and / or dispersible solid composition which is the subject of the present invention comprises at least one active substance. In a variant of the invention, said composition comprises a mixture of two, three, four or more different active substances. The substance (s) active (s) included (s) in the composition according to the invention can (wind) be any active ingredient having an activity in the fields of pharmaceutical, parapharmaceutical, cosmetic, nutraceutical, food supplements or agri-food. These active substances may be hydrophilic, lipophilic or amphiphilic. Advantageously, their average particle size distribution does not exceed 50 μm, in particular 30 μm, and more particularly 20 μm. In the context of the present invention, the particle size of a powder according to the invention is understood to mean the average size of the particles which constitute it. The average particle size can be measured by any conventional technique known per se. In particular, those skilled in the art may use a laser particle size measurement of the Beckman Coulter or Malvern type. The substance (s) active (s) capable (s) to be implemented in the composition according to the invention can (wind) be selected (s) among the active ingredients conventionally used in pharmacotherapy and especially in families Pharmacotherapeutic: allergology, anesthesia / resuscitation, oncology and hematology, cardiology and angiology, contraception and termination of pregnancy, dermatology, endocrinology, gastroenteroheopathology, gynecology and obstetrics, immunology and transplantation drugs, infectiology and parasitology, metabolism, diabetes and nutrition, neurology / psychiatry, ophthalmology, otolaryngology, pneumology, rheumatology, stomatology, toxicology, urology / nephrology, as well as among analgesics / anti-pyretic and antispasmodic, anti-inflammatory, diagnostic products, hemostatics and blood products and derivatives. In particular, the active substance (s) may be selected from the group consisting of the active ingredients that are useful or used in the treatment, prevention and / or prophylaxis of a pathology or a disease. a central nervous system disorder, a pathology or a gastric disorder or a pathology or disorder of an inflammatory nature and any other group of active principle requiring outpatient treatment. Advantageously, the substance (s) active (s) can (wind) be selected (s) from the group consisting of anti-inflammatory and including nonsteroidal anti-inflammatory drugs, anti-epileptics, antiparkinsonians, antimyasthenics antispastics, antimigraine agents, antiepileptics, neuroleptics, antidepressants, psychotropic drugs, anticholinesterase agents, NMDA receptor antagonists, antacids, gastric antisecretory agents, dopamine antagonists, antispasmodics, antimigraine agents, choleretic agents, hepatotropic agents, laxatives, vitamin A derivatives, antivirals, anticancer agents, analgesics, antiulcerics, antipsoriatic agents, antibiotics, cyclooxygenase inhibitors (COX inhibitors), sex hormones (for example, anti-estrogens, estrogens, progestins, androgens and antiandrogens, as examples and non-exhaustive, the substance (s) active (s) can (be) selected in the group consisting of acetazolamide, alclometasone dipropionate, acyclovir, adapalene, the agonist (3-3 adrenergic, alclomethasone dipropionate, alosetron, alprostadil, alprozolam, benzodiazepine alprozolam, amcinonide, amelene, 5-aminolevulinic acid, amoxicillin, androstanolone , A-4-androstenedione, aripipazole, bamethan sulfate + escine, betamethasone valerate, betamethasone dipropionate, bufexamac, buprenorphine, buspirone, caffeine, calcipotriol monohydrate, capravirine, caspofungin acetate, cefaclor, cetrimonium bromide, cilomilast, clobetasol propionate, clonazepan, clonidine, cloxacillin, coenzyme Q10, crilanomer, cyclosporine, cyproterone acetate, darifenacine, desogestrel, 3-keto-desogestrel, the desonide, the dexmedetomidi ne, dexpanthenol, diazepan, diclofenac, diflucortonol, difluprednate, diphenhydramine hydrochloride, donepezil, eletriptan, econazole nitrate, eptazocine, estradiol and its derivatives (hexahydrobenzoate estradiol, estradiol undecylate, estradiol valerate, ethinyl estradiol), erythromicin, esomeprazole, etoricoxib, ezetimide, fenoprofen, fentanyl, flubiprofen, pivalate flumetasone, fluocinolone acetonide, fluocinodine, fluocortolone, fluocortolone hexanoate, fluocortolone pivalate, growth hormone, hydrocortisone, hydrocortisone acetate, ibacitabine, ibuprofen, imiquimod, indomethacin, insulin, interferon a, isosorbide dinitrate, isotretinoin, ketoconazole, ketoprofen, ketorolac, ketotifen, lansoprazole, levonorgestrel in combination with ethinyl estradiol or with estradiol, lidocaine, lorazepan, mecamyl amine, medindolol, melagatran, mementin, methylphenidate, metronidazole, miconazole, miconazole nitrate, minoxidil, mitidlinide, molsidomine, naloxone, naproxen, nebivolol, nestorone, nicotine, S (-) nicotine, acid niflumide, nitroglycerin, norethisterone acetate, norethisterone enanthate, 7a-methyl-19-nortesterone, omapatrilat, omeprazole, orzel, oxybutinin, parecoxib, penciclovir, pergolide, benzoyl peroxide, phlorglucinol, physostigmine, piroxam, piroxicam, pitavastatin, povidone iodine, prazosin, prednisolone, progesterone, promestriene, prostaglandins, pyrazonibutasone , raloxifene, risperidone, rosuvastatin, rotigotine, roxithromycin, salbutamol, scopolamine, selegiline, substance P antagonist, sulfacetalmide, tazarotene, tegaserod, testosterone, dihydrotestosterone, cyclohexane testosterone propionate, thiatolserine, thiolstrinol, norelgestromin, triamsinolone, trinitrin, triptans such as frovatriptan, naratriptan, zolmitriptan, rizatriptan, sumatriptan, eletriptan and almotriptan, tretinoin and isotretinoin, triclocarban, trimethadione, tulobuterol, valacyclovir, valdecoxib, valproic acid, vidarabine monophosphate, viozan, voriconazole, salts and mixtures thereof.

The active substance (s) used in the context of the present invention may (also) be chosen from the active agents conventionally used in cosmetics, parapharmacy and food supplements. The contents of these assets are those conventionally used in the fields considered. Examples of cosmetic and parapharmaceutical active ingredients are emollients, humectants, pigments and dyes, anti-wrinkle agents (such as retinol), antifungal agents, anti-acne agents, fabric softeners, perfumes, vitamins and the like. their mixtures. Among the active ingredients for food supplements, mention may be made of vitamins such as vitamins A, B, E, C, B1, B2, B3, B6, B9, B12, B8H, B5,. minerals such as calcium, phosphorus, iron, magnesium, zinc, iodine, ...; carotenoids such as alpha-carotene, beta-carotene, gamma cartene, lutein, zeaxanthin, cryptoxanthin, lycopene, ...; phytoestrogens such as isoflavones (e.g., genistein, diadzein, biochanin A, formononetin); lignans (for example, enterolactone, enterodiol); coumestanes (eg, coumestrol); plant extracts and especially extracts of fennel, heather, blackcurrant, grape seeds, fucus, ginseng, green coffee, ginger, apple pectin, ...; oils such as evening primrose oil, wheat germ, borage, pumpkin seeds ...; clays such as diosmestite, montmorillonites ...; ferments, yeasts and their mixtures.

In the context of the present invention, it is clear that a mixture of active substances covers both a mixture of active substances of the same group (ie pharmaceutical active ingredients, cosmetic active ingredients, active ingredients for food supplements) than a mixture of substances. taken in at least two of the groups listed above. The substance (s) active (s) implemented in the composition according to the invention can (wind) be of natural, chemical, synthetic or biological origin. Indeed, the active substance (s) used in the composition according to the invention may be obtained by methods of chemical synthesis or genetic engineering which are well known in the art. skilled person. The substance (s) active (s) used in the composition according to the invention can (wind) be used (s) in the state after recovery of the medium in which they (s) is ( nt) in the natural state or not, via in particular an extraction. The active substance (s) used in the composition according to the invention may also be used after a prior transformation such as purification, dilution, filtration or concentration, drying, lyophilization or a process as described in the patent application FR 03 02802.

The person skilled in the art will know, depending on the active substance (or mixture of active substances) used what quantity of active substance (s) used (s) used and this depending on the end use of the composition according to the invention. Thus, the amount of substance (s) active (s) is comprised in the composition according to the invention between 0.1 and 60% by weight, in particular between 0.5 and 30% by weight, in particular between 0.75 and 10% by weight and, more particularly, between 1 and 5% by weight relative to the total weight of the composition.

A diluent with no known effect is used to complete the solid, orodispersible and / or dispersible pharmaceutical composition object of the present invention until a predetermined total volume containing the selected amount of active substance (s) is obtained.

The diluting agent without known effect in the composition according to the invention has sufficient binding properties dispensing the use of binding agent such as povidone, starch derivatives, polyvinyl alcohol or any other binding agent known by the art. skilled person. Thus, advantageously, the solid, orodispersible and / or dispersible composition according to the invention does not comprise a binding agent. The diluting agent with no known effect used in the context of the present invention has good flow and settling properties. By way of example, this diluting agent has a flow of less than 10 seconds and an apparent volume of less than 20 ml. The diluting agent without known effect used in the context of the present invention represents from 40 to 99% by weight, in particular from 50 to 95% by weight and, in particular, from 60 to 90% by weight relative to the weight. total of the composition according to the invention. The diluting agent without known effect used in the context of the present invention is chosen from cellulose powder, non-silicified microcrystalline cellulose, microcrystalline cellulose with a low water content (ie microcrystalline cellulose having a quantity in water less than 1.5% by weight relative to the total weight of the microcrystalline cellulose), cellulose acetate, di or tribasic calcium phosphate, calcium sulphate, dextrates, dextrins, hydrogenated vegetable oils, glyceryl palmitostearate polymethacrylate. These agents may be used alone or as a mixture and in particular in a mixture of two, three, four or more. Microcrystalline cellulose is preferentially chosen.

The term "disintegrating agent" is intended to mean any substance or mixture thereof which contributes essentially to the mechanical characteristics of disintegration in an aqueous medium of the tablets produced from the solid composition which is the subject of the present invention.

The disintegrating agent represents from 0.1 to 15% by weight, especially from 1 to 10% by weight and, in particular, from 2 to 6% by weight relative to the total weight of the composition. The disintegrating agent used in the context of the composition according to the invention is chosen from crospovidone (or crosslinked polyvinylpyrrolidone), croscarmellose (or sodium crosslinked carboxymethylcellulose), sodium starch glycolate, sodium alginate, and the like. hydroxypropyl cellulose, starch, pregelatinized starch, their derivatives and mixtures thereof. These agents may be used alone or as a mixture and in particular in a mixture of two, three, four or more. Crospovidone and croscarmellose are preferred disintegrants in the context of the present invention.

By sweetening agent is meant any substance or mixture of substances likely to significantly improve the compliance of this composition, and more particularly any substance or mixture of substances with no notorious effect capable of masking the unpleasant taste and bitterness of certain substances active. To be more effective and thus avoid the need to coat or lamination the active substance (s), the sweetening agent (s) present (s) a particle size less than 50} gym, better inferior to 30} gym, even better inferior to 10} gym. Thanks to the use of a sweetening agent with a particle size of less than 50 μm evenly distributed, the use of a coating agent or a film-coating agent is not necessary to mask the unpleasant flavors of certain active substances. The composition according to the invention may comprise a sweetening agent or a mixture of sweetening agents and in particular a mixture of two, three, four or more sweetening agent (s), provided that the percentage by weight of the agent sweetener or mixture of sweetening agents ranges from 0.05 to 10% by weight, in particular from 0.1 to 5% by weight and, in particular, from 0.5 to 2.5% by weight relative to the total weight of the composition. The sweetening agent (s) is (are) advantageously chosen from synthetic sweeteners and, more particularly, from gluconate, potassium acesulfame, sodium saccharin, lithium saccharinate, cyclamate, or mixtures thereof. Indeed, in the context of the present invention, synthetic sweeteners are not metabolized in the body with natural sweeteners and this to avoid adding an excipient with a known effect in the composition according to the invention.

In order to complete the organoleptic effect of the sweetening agent (s), the composition according to the invention may also comprise a flavoring agent or a mixture of flavoring agents. Thus, according to a preferred embodiment of the pharmaceutical composition according to the invention, the organoleptic characteristics are further improved by the addition of this (or these) flavoring agent (s).

Thus, the composition according to the invention may also comprise from 0.005 to 10% by weight, in particular from 0.05 to 8% by weight, in particular from 0.5 to 6% by weight and, more particularly from 0.75 to 4% by weight of a flavoring agent or a mixture of flavoring agents, relative to the total weight of the composition.

Preferably, the flavoring agent (s) is (are) chosen from natural flavors, natural identical flavors or artificial flavors. In particular, the flavoring agent (s) are chosen from a fruit aroma, a mint aroma, an anise aroma, a honey aroma, a vanilla aroma, a tea aroma and a verbena aroma. More particularly, the following flavoring agent (s) are used in the context of the present invention: apricot, apricot-orange, citrus, pineapple-coconut, anise, banana, cocoa, caramel, caramel-fruit, blackcurrant, cherry, cherry cherry, cherry-raspberry, lemon, lime-green, orange essence, orange blossom, strawberry, raspberry, passion fruit, forest fruits, orchard fruits, fruits red, red fruits / caramel, grenadine, currant, orange juice, tangerine, mango, mint, peppermint, mint-eucalyptus, honey, mirabelle, blackberry, blueberry, grapefruit, peach, pear, apple, plum, pulp orange, grape, licorice, rosemary-orange, tea, vanilla, verbena or violet. Advantageously, the flavoring agent (or the mixture of flavoring agents) is adsorbed on a suitable support before being incorporated in the pharmaceutical composition according to the invention, in the form of a powder of the previously impregnated support. Any type of conventional pharmacy support may be used for the flavoring agent, such as, for example, silica, starch or cellulose powder.

The composition according to the invention may comprise one or more flow agent (s) ensuring a homogeneous distribution of the active substance or mixture of active substances in the composition and a good flow of the final mixture. The flow agent or the mixture of flow agents represents from 0.001 to 1% by weight, in particular from 0.005% to 0.8% by weight and, in particular, from 0.01% to 0.5% by weight. by weight relative to the total weight of the composition. Among the flow agents that can be used in the context of the present invention, mention may be made of colloidal silica, silica dioxide, magnesium or calcium silicate and talc. In the context of the present invention, the colloidal silica is preferably chosen.

Finally, the composition according to the invention may further comprise a lubricating agent or a mixture thereof. At the time of manufacture of the tablet, a suitable amount of a lubricating agent or a mixture of lubricating agents is added to the outer layer of the latter and in particular to the final mixture of the composition according to the invention just before the submit to direct compression. Preferably, the appropriate amount of the lubricating agent is from 0.01 to 2% by weight, in particular from 0.05 to 1.5% by weight and, in particular, from 0.1 to 1% by weight relative to in total of the composition. The lubricating agent (s) is (are) advantageously chosen from magnesium stearate, stearic acid and its derivatives, calcium stearate, sodium stearate, sodium stearyl fumarate, and the like. sodium acetate, sodium oleate, sodium chlorate, sodium benzoate, glycerin behenate, polyethylene glycol, talc and hydrogenated vegetable oils. Sodium benzoate can also be used as a preservative and anti-bacterial agent. Magnesium stearate is one of the lubricating agents more preferably used in the composition according to the invention.

In addition, the composition may comprise a humectant or a mixture of humectants. In the context of the present invention, the term "humectant" is intended to mean any substance, in solid form, modifying the surface tension of water on the active substance in order to increase the wettability of the active substance in an aqueous medium. The humectant or the mixture of humectants represents from 0.01 to 5% by weight, especially from 0.05 to 2% by weight and, in particular, from 0.1 to 1% by weight relative to the weight. total of the composition. The humectant is chosen from dodecyl sulphate, sodium lauryl sulphate (SLS), a polyoxyethylenated polysorbitan ester, such as monooleate, monolaurate, monopalmitate, monostearate, sorbitan esters, polyoxyethylenated ethers, sodium dioctylsulfosuccinate ( DOSS), lecithin, sodium docusate, and mixtures thereof. Indeed, these agents can be used alone or in combination of two, three or four or more. Sodium lauryl sulfate is preferably chosen.

The composition according to the invention may also comprise other excipients of the adjuvant type such as dyes, salivation agents, preservatives, pH regulators, antioxidants, etc. The skilled person knows what type of compounds to use for each of the above classes of excipients and in what proportion, the only constraint is to choose excipients without known effect.

Preferably, the pharmaceutical composition according to the invention is particularly suitable for oral administration and, more particularly, adapted for ambulatory oral and sublingual use and / or for use after dispersion. Thus, the orodispersible and / or dispersible solid composition according to the invention is advantageously in unit dosage forms containing appropriate amounts of active substances, in particular pharmaceutically acceptable ones. Such amounts range from 0.05 to 2000 mg, especially from 0.1 to 1000 mg, in particular from 1 to 500 mg, and most particularly from 1 to 200 mg of active substance per unit dose. The unit dosage form preferred in the context of the present invention is a preparation packaged in tablet form and, more particularly, orodispersible and / or dispersible tablets. This tablet may be monolayer from a single homogeneous or multi-layer mixture from several mixtures. It being understood that, in the context of multi-layer or dual-core tablets, each mixture meeting the characteristics of the invention will constitute one of the layers of the tablet. In addition to the conventional tablet, the present invention may relate in particular to two-layer or three-layer tablets. In addition, the unit dosage form can be either such a tablet per se, or an appropriate number of such tablets. Such unit dosage forms are particularly suitable for one (or more) daily intake (s) depending on the application and in particular depending on the therapy, the phase of therapy or other.

The present invention also relates to the use of the solid, orodispersible and / or dispersible composition according to the present invention as previously defined as a medicament, as a dietary supplement or in cosmetics.

By virtue of the qualitative and quantitative composition of active principle and excipients described in the invention, a final formulation in the form of tablets can be easily prepared by a simple process of successive dilutions and then direct compression of the mixture of the active ingredient and the excipients, of which the pharmacotechnical characteristics are optimal. Preferably, a tablet according to the invention has a tensile strength of between 10 and 150 N, in particular between 20 and 100 N and, more particularly, between 30 and 60 N and is dispersed in distilled water at 20 to 100 N. ° C and / or disintegrates in the oral cavity in less than 3 minutes, especially in less than 2 minutes, in particular in less than 1 minute and even better in less than 20 s.

Finally, the subject of the present invention is a process for preparing an orodispersible and / or dispersible tablet comprising the steps of: 1) homogeneously mixing at least one active substance, at least one diluting agent without known effect, at least one disintegrating agent at least one sweetening agent having a particle size less than 50 μm as defined above and in the previously defined proportions and, optionally, one or more other excipients, 2) optionally sieving the mixture and / or during the preparation of said mixture and this, to remove unwanted agglomerates, 3) optionally lubricate said mixture by adding at least one lubricating agent as previously defined and in the previously defined proportions, 4) compressing said mixture which has optionally been sieved and / or lubricated in a compression machine provided with adequate punches to obtain an orodispersib tablet and / or dispersible delivering the desired amount of active substance.

The possible other excipients added to the mixture of the process of the invention comprise, in particular, the excipients previously described and, in particular, the flow, flavoring, coloring and humectant agents as previously defined and in the proportions previously defined. The mixture of ingredients (active agent and excipients) can be achieved by adding these ingredients either simultaneously or sequentially. The sequential addition of the ingredients makes it possible to introduce one or more sieving and / or lubrication steps during the mixing step.

In a first embodiment of the preparation method according to the invention, the step (1) of the latter may comprise the steps of: a) mixing at least one active substance as defined above and in the proportions previously defined with at least one flow agent as defined above and in the proportions previously defined, b) optionally, sieving the mixture of step (a), c) adding at least one diluent agent as previously defined and then mixing, d) optionally, sieving the mixture of step (c), e) adding to the optionally sieved mixture of step (d), at least one diluent agent as defined above, at least one disintegrating agent as previously defined and in the previously defined proportions, at least one sweetening agent having a particle size of less than 50 μm as defined above and in the previously defined proportions and, if appropriate, at least one dyeing agent as defined above and in the defined proportions, then mixing and at least one flavoring agent as previously defined and in the proportions previously defined, the diluting agents of steps (c) and (e) which are identical or different. being such that the final proportion of agent (s) diluent (s) in the final tablet is 40 to 99% by weight relative to the total weight of the tablet. This first form of implementation is in particular that which is illustrated in Figure 4.

In a second embodiment of the preparation method according to the invention, the step (1) of the latter may comprise the steps of: a ') mixing at least one active substance as previously defined and in the proportions previously defined with at least one flow agent as defined above and in the proportions previously defined, b ') optionally, sieving the mixture of step (a'), c ') adding at least one diluent agent such as previously defined, then mixing, optionally) sieving the mixture of step (c), e ') adding at least one diluent as previously defined then mixing, f') optionally sieving the mixture of the step ( e '), g') adding to the optionally sieved mixture of step (f '), at least one diluent agent as defined above, at least one disintegrating agent as defined previously and in the proportions previously defined, at least a sweetening agent having a particle size less than 50 μm as defined above and in the proportions previously defined and, optionally, at least one coloring agent as defined above and in the defined proportions, then mixing and at least one flavoring agent as defined above. and in the previously defined proportions, the same or different diluting agents of steps (c '), (e') and (g ') being such that the final proportion of agent (s) diluent (s) in the final tablet is from 40 to 99% by weight relative to the total weight of the tablet.

The mixture obtained at the end of steps (e) or (g ') is subjected to steps 2, 3 and 4 of the process as previously defined. The different ingredients added in steps (c), (e), (c '), (e') and (g ') of the processes can be sieved before they are added.

The two embodiments described above may have variants.

Thus, a first variant (i) relates to step (a) and step (a '). Indeed, it can be envisaged that said at least one active substance as defined above and in the proportions previously defined is mixed with a given amount of diluent before mixing with at least one flow agent as previously defined and in the proportions previously defined. The only condition for this variant is: in the context of the first previously defined embodiment, that the diluent used in this variant and the diluting agents of steps (c) and (e), which are identical or different, are such that the final proportion of agent (s) diluent (s) in the final tablet is 40 to 99% by weight relative to the total weight of the tablet; in the context of the second previously defined embodiment, that the diluting agent used in this variant and the diluting agents of steps (c '), (e') and (g '), which are identical or different, are such that the final proportion of agent (s) diluent (s) in the final tablet is 40 to 99% by weight relative to the total weight of the tablet.

A second variant relates to step (e) and step (g '). Indeed, it is conceivable that the ingredients added, during these steps, respectively to the mixtures of steps (d) and (f ') are added (ii) together after being mixed together with a diluent agent as previously defined and then optionally sieved, (iii) one after the other, each having been premixed with a diluent agent as previously defined and then optionally sieved, (iv) together after being mixed together with a diluent agent as previously defined and then optionally sieved certain ingredients having been premixed with a diluent agent as previously defined and then optionally sieved.

FIG. 1 illustrates a preparation method having variant (iii) for step (g ') and FIG. 3 illustrates variant (ii) for step (g') and FIG. 4 illustrates variant (iv) respectively. ) for step (e). Figure 6 illustrates a method of preparation with both variant (i) for step (a) and variant (iii) for step (e). The choice of the punches of the tablet machine, their shape and size, the operating conditions during any sieving or compression is routine work for the skilled person, as the choice of sieve size to be used depending on the nature of the ingredient or the mixture of ingredients to be sieved.

Surprisingly, it has been demonstrated that the qualitative and quantitative composition and its manufacturing method, according to the invention, made it possible to obtain a faster in vitro dissolution profile than the commercialized forms.

Thus, by virtue of the solid pharmaceutical composition and its method of manufacture, according to the invention, orodispersible and / or dispersible tablets can be prepared which have an in vitro dissolution profile in a pH 1.2 buffer solution with more than 75 % of active substance released in less than 5 min and in particular more than 90% of active substance released in less than 5 min. Even more surprisingly, it has been demonstrated that the qualitative and quantitative composition and its manufacturing method, according to the invention, make it possible to obtain in vivo pharmacokinetic profiles comparable to a commercially available orodispersible composition such as, for example, lyophilizates. oral. Other features and advantages of the present invention will become apparent on reading the examples given below by way of illustration and not limitation and with reference to the appended figures.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the manufacturing scheme used for the formulations containing risperidone (D 2 dopaminergic antagonist with a preferential action at the level of the limbic system) as an active principle and in accordance with a first variant of the method of preparation as previously defined. FIG. 2 shows the dissolution profiles obtained in vitro for formulations according to the invention and for commercial oral lyophilizates containing as active principle either 0.5 mg or 2 mg of risperidone. FIG. 3 shows the manufacturing scheme used for the formulations containing donepezil (a cholinesterase inhibitor which, by centrally increasing the acetylcholine concentrations in the synaptic cleft, would improve cognitive function during the course of the disease. Alzheimer) as an active ingredient and according to a second variant of the preparation method as defined above. FIG. 4 shows the manufacturing scheme used for the formulations containing donepezil as active principle and in accordance with a third variant of the preparation method as defined above. FIG. 5 shows the dissolution profiles obtained in vitro for formulations according to the invention containing as active ingredient either 5 mg or 10 mg of donepezil and for a specialty marketed at 10 mg of donepezil. FIG. 6 shows the manufacturing scheme used for the formulations containing nebivolol (cardioselective beta-blocker indicated in the treatment of hypertension) as an active principle and in accordance with a fourth variant of the preparation method as defined above. .

DETAILED DESCRIPTION OF PARTICULAR EMBODIMENTS Example 1 Orodispersible / dispersible compositions of risperidone obtained by a direct dilution / compression mixing process. A. Choice of Excipients The excipients selected in the context of Example 1 and Example 2 and, in general, within the context of the present invention, guarantee an industrial feasibility, a stable and safe end product. the patient (use of excipients with no known effect recorded in the Pharmacopoeia).

Microcrystalline Cellulose: This excipient is a diluent commonly used in the manufacture of tablets. Several types of microcrystalline cellulose are available. They differ in their mode of manufacture, particle size, residual moisture, flow, or other physical properties. For the development of an orodispersible / dispersible tablet, the choice fell on Vivapur 12 marketed by the company JRS. Indeed, it has a residual moisture of less than 5%, a good flow, a particle size distribution adapted to other components (average particle size of 180} gym) and good ability to direct compression. Any supply of equivalent quality may be substituted for this one.

Croscarmellose Sodium (or Carboxymethylcellulose Crosslinked): This excipient is a disintegrating agent generally used in dry mix at 2 to 5% in the formula. The croscarmellose sodium used during development is AcDiSol marketed by the company FMC Biopolymer. Any supply of equivalent quality may be substituted for this one.

Acesulfame Potassium: This intense sweetener is frequently used in pharmaceutical specialties. Acesulfame potassium enhances the flavors and enhances the effect of (or) flavor (s) used to mask the bad taste of the active substance. Potassium acesulfame used during development is provided by ACT. Any supply of equivalent quality may be substituted for this one.

Mint-peppery aroma: A mint flavoring has been selected to mask the unpleasant taste of the active substance. The peppermint flavor used during development is provided by IFF. Any supply of equivalent quality may be substituted for this one.

Hydrophilic Colloidal Silica: This excipient is used in the formula as a flow agent to allow a good distribution of the active substance. Thus, the use of colloidal silica makes it possible to correctly distribute the active substance in the mixture. The colloidal silica used is supplied by the company Degussa under the name Aerosil 200. Any supply of equivalent quality can replace this one.

Magnesium Stearate: This excipient is commonly used in pharmaceutical specialties for its lubricating properties. The magnesium stearate of plant origin used during development is provided by the company PETER GREVEN under the name Liga MF2V. Any supply of equivalent quality may be substituted for this one.

E172 dye: This natural iron oxide pigment makes it possible to obtain a composition with a pink coloring. The dye E172 used during development is supplied by BASF under the name Sicovit Rouge 30.

B. Compositions and characteristics of the formulas produced Table 1 below shows, for each formulation made in the context of the present invention, its composition and its characteristics.

Risperidone (API) 0.500 1,000 2,000 3,000 4,000 1,00 Hydrophilic colloidal silica 0.005 0.010 0.020 0.030 0.040 0.01 Microcrystalline cellulose qs qs qs qs qs qs Carboxymethycellulose 2.500 5,000 10,000 15,000 20,000 5.00 crosslinked 0.625 1,250 2,500 3,750 5,000 1,25 Aroma Peppermint Acesulfame Potassium 1,000 2,000 4,000 6,000 8,000 2,000 Dye E172 0.010 0.020 0.040 0.060 0.080 0.02 Magnesium Stearate 0.250 0.500 1,000 1.500 2,000 0.50 Residual Moisture (%) 4.5 - 5.5 Flow ( s) <10 Bulk density 0.35 - 0.55 Appearance Pink powder Format of punches Flat Flat Flat, 0 Flat, 0 bevel chamfer 10R12 30 °, 0 30 °, 0 9R11 mm 5.5 mm 6.5 mm mm Thickness 1.75-2.15 2.50-2, 90 3.45-3.85 4.30-4.70 Breaking Strength (N) 30-50 45-65 45-65 55-75 Disintegration - Water R 37 ° C (s) <10 <10 <10 <10 Dispersion - Water R 20 ° C (s) <15 <15 <15 <15 Finesse of dispersion Conform Conform Conform Conform Friability (%) <0,5 < 0.5 <0.5 <0.5 Uniformity of content Con form Compliant Conform Conform In vitro dissolution 75% 75% 75% 75% (at 15 min in pH 1.2 buffer) Flat, 0 11R11 mm 5.25-5.65 55-75 <10 <15 Conform <0.5 Conform 75% Theoretical mass of the tablet (mg) 50.00 400.00 300.00 200.00 100.00 Table 1 C. Manufacturing process Figure 1 shows the manufacturing scheme used for the risperidone formulations .

STEP 1: PRE-MIXING Mix all of the amount of flow agent with all of the risperidone (API) and 25% of the amount of polyethylene bag diluent, 10 turns. STEP 2: MIXING 1 Introduce into a Rho wheel type blender, 25% of the quantity of the diluent and then the pre-mix, previously sieved on an 800 mesh grid.

Mix together for 5 min at about 10 rpm. STEP 3: MIXING 2 Add to mixture 1 the balance of the diluent, mix together for 5 min at about 10 rpm. STEP 4: MIXING 3 Add to the mixture 2, the dye premixed with diluent and sieved on a grid opening of mesh between 0.250 and 0.500 mm, the flavor premixed with thinner and sieved on a grid of opening of mesh of 0.800 mm, the sweetener premixed with diluent and sieved on a grid opening of mesh between 0.500 and 0.800 mm, the disintegrating agent premixed with diluent and then the balance of diluent. Mix together for 15 min at about 10 rpm.

STEP 5: FINAL MIXING Add to the mixture 3 the lubricant previously sieved on a grid opening of mesh 0.800 mm.

Mix for 5 minutes at about 10 rpm. STEP 6: COMPRESSION Equip the machine to compress appropriate punches and adjust it to obtain the characteristics of the tablets described according to the invention.

STEP 7: PACKAGING Pack tablets into PVCPVDC / Aluminum thermoformed blister.

D. Comparative In Vitro Dissolution Study The operating conditions used for this study are as follows: Equipment Dissolutest Sotax AT7 Lambda Spectrophotometer 20 Method: HPLC Assayed Compound: Risperidone Tank Volume: 1000 ml Medium: HC1 0.1N Buffer Rotation axis: 50 rpm The in vitro dissolution profiles obtained for two formulations according to the invention and for two commercial oral lyophilizates based on risperidone (0.5 mg and 2 mg) are presented in FIG. 2.

EXAMPLE 2 Dilsepezil Orodispersible / Dispersible Compositions Obtained by a Direct Dilution / Compression Mixing Process A. Selection of Excipients Microcrystalline Cellulose: This excipient is a diluent commonly used in the manufacture of tablets. Several grades are available, the choice fell on the Vivapur 14 marketed by the company JRS. Vivapur 14 is equivalent to Grade 12 but with a very low moisture content of less than 1.5%. This excipient is particularly suitable for active ingredients or compositions sensitive to moisture quality supply. Any equivalent can substitute for this one.

Croscarmellose sodium: cf. example 1.

Pregelatinized Corn Starch: This excipient is a disintegrating agent used for making tablets. For the development of an orodispersible / dispersible tablet, the choice fell on the Starch 1500 marketed by the company COLORCON. Thanks to its rheological properties (flow, granulometry ...), this excipient is particularly suitable for direct compression. Any supply of equivalent quality may be substituted for this one.

Sodium Starch Glycolate: This effective and inexpensive disintegrating agent is particularly suitable for direct compression. The sodium starch glycolate used during the development of the composition is supplied by JRS Pharma under the trade name Explotab. Any supply of equivalent quality may be substituted for this one.

Acesulfame potassium: cf. example 1.

Saccharin Sodium: Sodium saccharin is an intense sweetener used in beverages, food products, table top sweeteners and pharmaceutical formulations. Sodium saccharin is considerably more soluble in water than saccharin and also more frequently used in pharmaceutical formulations. Its sweetening power is approximately 300 times more potent than sugar. Sodium saccharin enhances the flavors and can be used to mask some unpleasant taste characteristics. All these characteristics are in line with the objective of developing an orodispersible and / or dispersible tablet. The COOPER laboratory supplies sodium saccharin used during development.

Any supply of equivalent quality may be substituted for this one.

Mint-pepper aroma: cf. example 1.

Hydrophobic anhydrous colloidal silica: This excipient is used in the formula as a flow agent to allow a good distribution of the active substance. Thus, the use of colloidal silica makes it possible to correctly distribute the active substance in the mixture. The colloidal silica used is provided by Degussa under the name Aerosil R972. This quality has hydrophobic properties and allows the orodispersible and / or dispersible tablet to be less sensitive to the phenomenon of moisture absorption. Any supply of equivalent quality may be substituted for this one.

Magnesium stearate: cf. example 1.

Colorant E172: cf. example 1.

B. Compositions and characteristics of the formulas made Table 2 below shows, for each formulation made in the context of the present invention, its composition and its characteristics.

Donepezil 3.57 3.57 2.04 3.57 Low microcrystalline cellulose 88.78 88.78 Qs Qs moisture content 5.00 Pregelatinized corn starch Acesulfame potassium 1.00 1.00 1.00 AcDiSol 5, 00 2.50 2.50 Explotab 2.50 2.50 Saccharin Sodium 1.00 E172 Coloring 0.05 0.05 0.50 Peppermint Aroma 1.00 1.00 0.75 0.75 Hydrophobic Colloidal Silica 0, 10 0.10 0.10 0.10 Magnesium stearate 0.50 0.50 0.50 0.50

.................................................. ........................ DTD: ........................ ................ Flow (s) <10 <10 <10 <10 Table 2..DTD: C. Manufacturing process Figures 3 and 4 show two production diagrams put for the donepezil formulations.

The preparation method which is the subject of FIG. 3 is described in more detail below. STEP 1: PRE-MIXING Mix all of the amount of flow agent with all of donepezil (API) and Format punches Flat, 0 9.5 mm Flat, 0 9.5 mm Flat, 0 9 mm Flat, 0 9 mm Breaking Strength (N) Disintegration -Water R 37 ° C - (s) Dispersion -Water R 20 ° C (s) Scattering Frivability (%) 48 61.20 71.80 44.50 13 4 7 <10 <10 <10 <10 in accordance with conformity according to conformity 0.31 0.05 <0.01 <0.01 Theoretical mass of the tablet (mg) 280 280 245 280 25% of the quantity of diluent in polyethylene bag , 10 reversals. STEP 2: MIXING 1 In a Rho wheel mixer, add 25% of the quantity of the diluent and then pre-mix, previously sieved on a grid with a mesh size of 0.500 mm. Mix together for 5 min at about 10 rpm. STEP 3: MIXING 2 Add to mixture 1 the balance of the diluent, mix together for 5 min at about 10 rpm. STEP 4: MIXING 3 Add to the mixture 2, the dye, the flavor, the sweetener premixed with diluent and sieved on a grid of opening of mesh 0.500 mm then the balance of diluent and the disintegrating agent. Mix together for 15 min at about 10 rpm. STEP 5: FINAL MIXING Add to the mixture 3 the lubricant previously sieved on a grid opening of mesh 0.500 mm. Mix for 5 minutes at about 10 rpm. STEP 6: COMPRESSION Equip the machine to compress appropriate punches and adjust it so as to obtain the characteristics of the tablets described according to the invention. STEP 7: PACKAGING Pack tablets into PVCPVDC / Aluminum thermoformed blister. The preparation process of FIG. 4 differs from the above method in that steps 1 and 2 are carried out simultaneously by mixing the flow agent and the total donepezil with 50% diluent.

D. Comparative In Vitro Dissolution Study The operating conditions used for this study are the following: Equipment Dissolutest Sotax AT7 Lambda Spectrophotometer 20 Method: HPLC Compound Assayed: Donepezil Vial Volume: 1000 ml Medium: Buffer pH 1, 2 Rotation axis: 75 rpm

The in vitro dissolution profiles obtained for two formulations according to the invention containing as active principle either 5 mg or 10 mg of donepezil and a specialty marketed at 10 mg of donepezil are shown in FIG.

Example 3 Orodispersible / dispersible Nebivolol Compositions Obtained by a Direct Dilution / Compression Mixing Process A. Selection of Excipients The excipients present in the Nebivolol formulation are described in Example 2. B. Compositions and Formula Characteristics Table 3 below shows, for the formulation carried out in the context of the present invention, its composition and characteristics. This composition is applicable whatever the desired dosage (1.25; 2.5; 5; 10 mg ...). Nebivolol 2.50 Low Moisture Microcrystalline Cellulose 1.25 Acesulfame Potassium AcDiSol 5.00 Aroma Peppermint 2.00 Hydrophilic Colloidal Silica 0.10 Magnesium Stearate 0.50 Flow <10 Table 3 Average Mass (mg) 51.96 404.50 Uniformity of mass Conforms Conforms Resistance to break (N) 35 75 Disintegration - Water R 37 ° C (s)) 7s 10s Dimensions thickness (mm) Diameter (mm) Table 4

C. Production Process Figure 6 shows a flow chart for the nebivolol formulations. 1.78 5.56 3.48 11.44 The preparation method which is the subject of FIG. 6 is described in more detail below. STEP 1: PREMIX Mix all Nebivolol (API) with an equivalent volume of diluent in a Rhoe Wheel type mixer. STEP 2: MIXING 1 Add flow agent (glidant) to the premix 10 in a Rhoe Wheel type mixer. Mix together for 5 min at about 10 rpm. STEP 3: MIXING 2 Add to mixture 1, 25% diluent, mix together for 5 min at about 10 rpm. STEP 4: MIXING 3 Add to mixture 2, the pre-mixed flavor with an equivalent volume of diluent and sieved on a grid opening of 0.500 mm mesh, the sweetener also premixed and sieved on a grid of 20 ml. mesh opening of 0.500 mm with an equivalent volume of diluent and then the balance of diluent and the disintegrating agent. Mix together for 15 min at about 10 rpm. STEP 5: FINAL MIXING Add to the mixture 3 the lubricant previously sieved on a grid opening of mesh 0.500 mm. Mix for 5 minutes at about 10 rpm. 48

STEP 6: COMPRESSION Equip the machine to compress appropriate punches and adjust it to obtain the characteristics of the tablets described according to the invention.

STEP 7: PACKAGING Pack tablets into PVCPVDC / Aluminum thermoformed blister.

Claims (16)

1) A solid, orodispersible and / or dispersible composition, without excipient with known effect, comprising: a) from 0.1 to 60% by weight of at least one active substance, b) from 40 to 99% by weight of minus a diluting agent with no known effect; c) from 0.1 to 15% by weight of at least one disintegrating agent; and d) from 0.05 to 10% by weight of at least one sweetening agent with a particle size less than 50 μm, the percentages by weight being expressed relative to the total weight of said composition. 2) Composition according to claim 1, characterized in that said active substance is an active ingredient having an activity in the pharmaceutical, parapharmaceutical, cosmetic, nutraceutical, food or agri-food supplements. 3) Composition according to any one of claims 1 or 2, characterized in that said active substance is selected from the active ingredients of the following pharmacotherapeutic families: allergology, anesthesia / resuscitation, oncology and hematology, cardiology and angiology, contraception 30 and pregnancy termination, dermatology, endocrinology, gastroentero-hepathology, gynecology and obstetrics, immunology and transplantation drugs, infectiology and parasitology, metabolism, diabetes and nutrition, neurology / psychiatry, ophthalmology, otolaryngology, pneumology, rheumatology, stomatology, toxicology, urology / nephrology, as well as among analgesics / anti-pyretic and antispasmodic, anti-inflammatory, diagnostic products, hemostatics and blood products and derivatives. 4) Composition according to any one of claims 1 or 2, characterized in that said active substance is selected from emollients, humectants, pigments and dyes, anti-wrinkle agents, antifungal agents, anti-acne agents, fabric softeners , perfumes, vitamins and their mixtures. 5) Composition according to any one of claims 1 or 2, characterized in that said active substance is selected from vitamins, minerals, carotenoids, phytoestrogens, plant extracts, clays, ferments, yeasts and their mixtures. 6) Composition according to any one of claims 1 to 5, characterized in that said diluent is selected from cellulose powder, non-silicified microcrystalline cellulose, microcrystalline cellulose with low water content, cellulose acetate, di or tribasic calcium phosphate, calcium sulphate, dextrates, dextrins, hydrogenated vegetable oils, glyceryl palmitostearate, polymethacrylate. 7) Composition according to any one of claims 1 to 6, characterized in that said disintegrating agent is selected from crospovidone, croscarmellose, sodium starch glycolate, sodium alginate, hydroxypropyl cellulose, starch, pregelatinized starch, their derivatives and their mixtures. 8) Composition according to any one of claims 1 to 7, characterized in that said sweetening agent is chosen from synthetic sweeteners and, more particularly from gluconate, acesulfame potassium, sodium saccharinate, sodium saccharinate. lithium, cyclamate, or mixtures thereof. 9) Composition according to any one of claims 1 to 8, characterized in that said composition comprises from 0.005 to 10% by weight of a flavoring agent or a mixture of flavoring agents, relative to the total weight of the composition. 10) Composition according to any one of claims 1 to 9, characterized in that said composition comprises from 0.001 to 1% by weight of one or more flow agent (s), relative to the total weight of the composition . 11) Composition according to any one of claims 1 to 10, characterized in that said composition comprises from 0.01 to 2% by weight of a lubricating agent or a mixture of lubricating agents, relative to the total weight of the composition. 12) Composition according to any one of the preceding claims, characterized in that said composition comprises from 0.01 to 5 by weight of a humectant or a mixture of humectants, relative to the total weight of the composition . 13) Composition according to any one of the preceding claims for its use as a medicament, as a dietary supplement or in cosmetics. 20 14) A method of preparing an orodispersible and / or dispersible tablet comprising the steps of: (1) homogeneously mixing at least one active substance, at least one diluent with no known effect, at least one disintegrating agent, at least one a sweetening agent having a particle size of less than 50 μm as defined in claims 1 to 8 and optionally one or more other excipients, (2) optionally sieving the mixture and / or being in progress for preparing said mixture, (3) optionally lubricating said mixture by adding at least one lubricating agent as defined in claim 11, (4) compressing said mixture which has optionally been sieved and / or lubricated in a punch machine with punches suitable for obtaining an orodispersible and / or dispersible tablet delivering the desired amount of active substance. 15) A method of preparation according to claim 14, characterized in that it comprises the steps of: (a) mixing at least one active substance as defined in claims 1 to 5, with at least one flow agent such as as defined in claim 10, (b) optionally sieving the mixture of step (a), (c) adding at least one diluent as defined in claims 1 and 6 and then mixing, (d) optionally sieving the mixture of step (c), (e) adding to the optionally screened mixture of step (d), at least one diluent agent as defined in claims 1 and 6, at least one disintegrating agent as defined in 1 and 7, at least one sweetening agent having a particle size less than 50 μm as defined in claims 1 and 8, the diluents of steps (c) and (e) being identical or different being such that the final proportion of agent (s) diluent (s) in the final tablet is d e 40 to 99% by weight relative to the total weight of the tablet. 16) A method of preparation according to claim 14, characterized in that it comprises the steps of: (a ') mixing at least one active substance as defined in claims 1 to 5, with at least one flow agent as defined in claim 10, (b ') optionally, sieving the mixture of step (a'), (c ') adding at least one diluent as defined in claims 1 and 6 and then mixing, (d') ) optionally, sieving the mixture of step (c), (e ') adding at least one diluent as defined in claims 1 and 6 and then mixing, (f') optionally, sieving the mixture of step (e) (g ') adding to the optionally screened mixture of step (f'), at least one diluent as defined in claims 1 and 6, at least one disintegrating agent as defined in claims 1 and 7, at least one sweetening agent having a particle size of less than 50 μm as defined in claims 1 e t 8, the diluents of steps (c '), (e') and (g ') identical or different being such that the final proportion of agent (s) diluent (s) in the final tablet is 40 to 99 % by weight relative to the total weight of the tablet.